From Bioinformatikpedia

Phenylketonuria (PKU) is an inborn metabolic disorder and is caused by different mutations in the enzyme phenylalanine hydroxylase (PAH), which is responsible for the alteration of phenylalanine to tyrosine. Untreated PKU can lead to psychotic disorders and the postnatal development of the brain can be harmed.


PKU results in enrichment of phenylalanine and decrease of tyrosine, whereby other features of the phenylalanine metabolism pathway are affected like the production of melanin. Thus symptoms like fair skin, light hair and blue or sometimes even red eyes can occur. Additionally there can be mousy odour, eczema, epilepsy and perceptible posture changes. In some cases the concerned persons show psychotic disorders, ADHD (attention-deficit hyperactivity disorder), Aggressions, autistic features, Hyperactivity and Self-harm (Self-mutilation).

There are two different PKU variants defined:

  • Classical Phenylketonuria is caused by mutation/s in the PAH gene (precisely described here)
  • Atypical (mild) Phenylketonuria is a deficiency of the tetrahydrobiopterin (BH4), a cofactor of the enzyme phenylalanine hydroxylase


See also description of this disease in


After birth every child is tested with a newborn-screening, where some disorders are analysed. If a higher concentration of phenylalanine or a bad ratio of phenylalanine and tyrosine is found, PKU is diagnosed and the patient can be treated as followed:

  • Special low phenylalanine diet for the whole life (routine treatment; constrains in meat, fish, eggs, nuts, legumes and milk products and careful usage in starchy food)
    • Maternal PKU: If women with phenylketonuria wish to have a child, they have to do a strict diet before and during pregnancy.
  • Tyrosine enriched food or medicaments
  • Intake of the enzyme PAL (phenylalanine ammonia lyase), which converts phenylalanine to a harmless metabolite
  • Tetrahydrobiopterin (only for mild PKU)


Biochemical disease mechanism

<figure id="pku_path">

Simplified disease pathway showing that PKU is affected on the beginning of the process thereby causing symptoms of other diseases as well. (Cf. german wikipedia)


  • The symptoms of PKU are caused by the complete or partial defected catalysing of phenylalanine to tyrosine.
  • As it occurs at the beginning of the phenylalanine metabolism pathway other metabolic diseases are associated like Albinism or Cretinism (<xr id="pku_path"/>)
  • PKU was named after the phenylketone (phenylpyruvate) in which phenylalanine is converted.
  • Protein phenylalanine hydroxylase:
    • is expressed in liver,
    • has a sequence length of 452 aa,
    • is encoded by the gene PAH (see Genomic information) on chromosome 12.

<figure id="metPath">

Phenyalanine metabolism pathway(KEGG)


Mutations and Genomic information

Genomic information

<figure id="chr12">

Chromosome 12: red box indicates location of the PAH gene (Ensembl)


PKU is an autosomal recessive disorder which can be caused by 400 different known mutations on the PAH gene. This gene lies on the human chromosome 12 (<xr id="chr12"/>) and consists of 13 exons. Most common are missense mutations, but also nonsense and silent mutations can be found. Normally the enzyme phenylalanine hydroxylase converts phenylalanine into tyrosine. If this pathway is disturbed, it is transformed to phenylpyruvic acid which constrains pyruvate decarboxylase in the brain (<xr id="hydrox"/>). This seems to be the reason for the mental disorders.

<figure id="hydrox">

Hydroxylation of phenylalanine to tyrosine and penylpyruvic acid (Davidson College)


Reference sequence

The Uniprot entry for PAH P00439 gives the protein sequence used as reference in this practical:

>sp|P00439|PH4H_HUMAN Phenylalanine-4-hydroxylase OS=Homo sapiens GN=PAH PE=1 SV=1

3D structure

</figure> </figure>
<figure id="1j8u">
3D structure of PAH using the pdb structure 1J8U that includes two ligands (H4B - C9H15N5O3 and Fe(II) ).
<figure id="2pah">
3D structure of PAH using the pdb structure 2PAH as tetramer with ligands Fe(III).

Database identifiers

In <xr id="databases"/> most databases containing information about PAH or PKU itself used for this practical can be viewed. For the structures found in RSCB there are a lot of different entries concerning PAH. The two IDs represent the structures used by us. <figtable id="databases">

Database PAH-ID
UniProt P00439
Ensembl ENSG00000171759
OMIM 612349 (PAH), 261600 (PKU)



Task 2: Sequence searches and multiple sequence alignments

Task 3: Sequence-based predictions

Task 4: Structural Alignments

Task 5: Homology based structure prediction

Task 6: Protein structure prediction

Task 7: Researching SNPs

Task 8: Sequence-based mutation analysis

Task 9: Structure-based mutation analysis

Task 10: Normal mode analysis